Analysis of current testing practices for biallelic MUTYH mutations in MUTYH-associated polyposis.

Landon M1, Ceulemans S, Saraiya DS, Strike B, Arnell C, Burbidge LA, Moyes K, Theisen A, Fernandes PH, Ji JQ, Abbott B, Kaldate RR, Roa B.

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Abstract

MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome caused by biallelic mutations in the base excision repair gene MUTYH. Due to potential limitations in the MAP testing strategy and testing criteria, it is possible that MAP is being under-identified both genotypically and phenotypically. To determine whether full sequencing of MUTYH would increase clinical sensitivity over a founder mutation strategy, a retrospective analysis of two datasets from a commercial clinical laboratory was performed. The first cohort contained 1,522 individuals who received MUTYH analysis for two founder mutations with subsequent full-gene sequencing. Eighty-five biallelic individuals were identified; 47 carried two founder mutations, 17 carried one founder mutation and one mutation identified on full sequencing, and 21 carried biallelic mutations identified only on full sequencing. The second cohort contained 921 patients with colorectal cancer <50 years and <10 reported colorectal adenomas who had undergone MUTYH mutation testing. In this cohort, 19/921 (2.1%) individuals were identified as biallelic MUTYH carriers. Of these, 13 did not have a personal or family history of polyps and would not have met guidelines for MUTYH testing. These results suggest that individuals with biallelic MUTYH mutations are under-ascertained based on both genotype and phenotype under current standard testing practices.